Moderate-severe traumatic brain injury (TBI) often causes neuronal death and neurocognitive impairments, with both immature and mature neurons being vulnerable to the injury. The endoplasmic reticulum (ER) plays a major role in the folding of membrane and secreted proteins and in calcium storage and intracellular calcium homeostasis. Its function can disrupted in response to decreased in response to a number of stimuli including reduced glucose levels, hypoxia, and altered calcium levels, all of which have been observed after TBI. Disrupted ER function (often referred to as ER stress) can result in the accumulation of misfolded proteins. One of the signaling pathways activated in response to ER stress is double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase (Perk). Once activated, Perk phosphorylates the translation initiation factor eIF2a, which acts to reduce global protein synthesis while permitting the synthesis of chaperones involved in protein folding. If ER function cannot be restored, Perk leads to the increased expression of CCAAT/enhancer-binding protein homologous protein (CHOP), a mediator of cell death. We have observed that TBI increases eIF2a phosphorylation and enhances CHOP expression. In order to examine the translational potential of targeting Perk-eIF2a-CHOP pathway, we have obtained preliminary experimental results to indicate that post injury administration of guanabenz (a FDA-approved drug that acts to inhibit eIF2a phosphatase) reduces neuronal loss and improves neurocognitive outcome. Furthermore, post-injury administration a chemical chaperone (4-phenylbuteric acid (4-PBA), an FDA-approved drug) also improved outcome. Based on these and other observations, we propose to test the hypothesis that post-TBI administration of guanabenz, 4-PBA, and their combination will effectively reduce loss of both mature and immature neurons and improve neurocognitive function. Aim 1: To determine efficacy of guanabenz and its therapeutic time window. Aim 2: To define the optimal dose and therapeutic time window for 4-PBA. Aim 3: To evaluate if the combination of guanabenz and 4-PBA is more efficacious. The results from these studies provide the basis for future clinical studies to determine if individual drugs alone or in combination can be used to improve outcome after TBI.